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Talk:Christina/@comment-75.38.169.29-20130427194328
The conversion from a non-tumorigenic state to a metastatic one is of critical interest in cancer cell biology, as most deaths from cancer occur due to metastasis1. Typically, we think of the activation of metastasis as one of the hallmarks of cancer2 and as a highly regulated, multistep process defined by a loss of cell adhesion due to reduced expression of cell adhesion molecules such as E-cadherin, degradation of the extracellular matrix (ECM), conversion to a motile phenotype, vascular infiltration, exit and colonization to a new organ site (i.e., intra- and extravasation), dormancy, and re-activation. From a physical sciences perspective, metastasis can be viewed as a “phase” transition, albeit occuring far from thermodynamic equilibrium3. Though this transition has been the focus of much cancer biology research, there is still an incomplete understanding of this phase change, in particular, the physical biology of the metastatic state of a cell compared to its pre-malignant state. Understanding the physical forces that metastatic cells experience and overcome in their microenvironment may improve our ability to target this key step in tumor progression. The newly formed Physical Sciences-Oncology Centers (PS-OC) Network, sponsored by and under the auspices of the Office of Physical Sciences-Oncology at the National Cancer Institute (OPSO/NCI), is a multidisciplinary network of twelve research centers across the US formed, in part, to test the fundamental hypothesis that physical processes (e.g., mechanics, dynamics) play a critical role in cancer initiation and metastasis. The PS-OC Network brings analytic techniques and perspectives from the physical sciences to the interpretation of biological data and consists of physicists, engineers, mathematicians, chemists, cancer biologists, and computational scientists. The goal of the PS-OC Network is to better understand the physical and chemical forces that shape and govern the emergence and behavior of cancer at all length scales. The study described in this manuscript focused on physical changes associated with metastasis. A controlled set of comparative studies of two cell lines that are extensively used as cell models of cancer metastasis and straddle the metastatic transition was undertaken by the PS-OC Network. The cell lines analyzed were the immortalized human breast epithelial cell line MCF-10A, representing a non-tumorigenic state, and the human metastatic breast cell line MDA-MB-231, representing a malignant state. Distinguishing features of the adherent, non-transformed, MCF-10A cells are their lack of tumorigenicity in nude mice, lack of anchorage-independent growth, and dependence on growth factors4. In contrast, MDA-MB-231 cells5 form highly malignant, invasive tumors in vivo, are resistant to chemotherapy drugs such as paclitaxel, exhibit anchorage-independent growth, and grow independently of growth factors. Although MCF-10A cells have wild-type p53 and MDA-MB-231 cells have mutant p53, both cell lines are negative for the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)6, 7. To ensure that data generated across the multiple PS-OC laboratories could be integrated, culture guidelines, common culture reagents, and the two fully characterized, karyotyped cell lines were distributed to PS-OC laboratories. This minimized phenotypic and genotypic drift. After demonstration of growth uniformity, the cells were evaluated by a battery of physical measurements, as outlined in Table 1, encompassing complementary physical, biochemical, and molecular assays, to establish a metastatic signature across multiple length scales, including the molecular, subcellular, cellular, and tumor length scales. Novel biophysical techniques interrogated classic phenotypic ‘hallmark’ properties of the two cell lines (e.g., morphology, motility, stress responses) and physical cell properties (e.g., shear rheology). A novel model-based regulatory network approach was used to generate hypotheses of linkages between molecular and physical signatures of the cell lines. By interrogating this one-of-a-kind dataset, this pilot study provides insight into intrinsic differences in the physical properties of metastatic cancer cells vs. their non-tumorigenic counterparts, while demonstrating the importance of the technologies employed from the physical sciences and the value of a network approach to the study of cancer biology.